6,11-4C-bicyclic 9a-azalide derivatives

ABSTRACT

The present invention discloses compounds of formula I, or pharmaceutically acceptable salts, esters, or prodrugs thereof:                    
     which exhibit antibacterial properties. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject in need of antibiotic treatment. The invention also relates to methods of treating a bacterial infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The invention further includes process by which to make the compounds of the present invention.

TECHNICAL FIELD

The present invention relates to novel semisynthetic macrolides havingantibacterial activity and useful in the treatment and prevention ofbacterial infections. More particularly, the invention relates to6,11-4C-bicyclic 9a-azalide derivatives, compositions comprising suchcompounds, methods for using the same, and processes by which to makesuch compounds.

BACKGROUND OF THE INVENTION

Macrolide antibacterial agents are widely used to treat and preventbacterial infections. However, the discovery of bacterial strains whichhave resistance or insufficient susceptibility to macrolideantibacterial agents has promoted the development of compounds withmodified or improved profiles of antibiotic activity. One such class ofcompounds is azalides, which includes azithromycin, described in U.S.Pat. Nos. 4,474,768 and 4,517,359. Azalides are macrolide antibacterialagents with a ring structure similar to the erythronolide A or B,however azalides possess a substituted or unsubstituted nitrogen moietyat the 9a position as illustrated in the following structure:

The potential for azalides to display modified or improved profiles forantibiotic activity has spawned extensive research to identifyadditional azalide derivatives with enhanced clinical properties. Thefollowing are examples of current efforts in azalide research:

PCT Application WO98/56801, published Dec. 17, 1998 discloses a seriesof 9a-(N-(alkyl))-azalide erythromycin A derivatives and a series of9a-(N—(alkyl))-azalide 6-O-methylerythromycin A derivatives;

PCT Application WO98/56802, published Dec. 17, 1998 discloses a seriesof 9a-(N—(H))-azalide erythromycin A derivatives and a series of9a-(N—(H))-azalide 6-O-methylerythromycin A derivatives;

PCT Application WO99/00124, published Jan. 7, 1999 discloses a series of9a-(N—(R_(n)))-azalide 3-thioxoerythromycin A derivatives and a seriesof 9a-(N—(R_(n)))-azalide 6-O-methyl 3-oxoerythrmycin A derivatives,wherein R_(n) is an optionally substituted alkyl or heteroalkyl;

PCT Application WO99/00125, published Jan. 7, 1999 discloses a series of9a-(N—(R_(n)))-azalide 3-oxoerythromycin A derivatives and a series of9a-(N—(R_(n)))-azalide 6-O-methyl 3-oxoerythromycin A derivatives,wherein R_(n) is an optionally substituted alkyl or heteroalkyl; and

U.S. Pat. No. 5,686,587 discloses a synthesis of azithromycin comprisingintroducing a 9a-(N(H))-moiety to erythromycin A by oxime formation,Beckmann rearrangement, reduction, and methylation.

SUMMARY OF THE INVENTION

The present invention provides a novel class of 6,11-4C-bicyclic9a-azalide compounds, or a pharmaceutically-acceptable salt, ester, orprodrug thereof, pharmaceutical compositions comprising at least onecompound of the present invention, methods of treating a bacterialinfection in a subject by administering said pharmaceuticalcompositions, and processes of making the compounds of the presentinvention.

In one embodiment of the present invention there are disclosed compoundsof formula I:

as well as the pharmaceutically acceptable salts, esters and prodrugsthereof, wherein:

W is

(a) —CH₂—C(A)═C(B)—CH₂—, wherein, A and B are independently selectedfrom:

1. hydrogen;

2. deuterium;

3. halogen;

4. R₁, wherein R₁ is selected from:

a. —C₁-C₆ alkyl, optionally substituted with one or more substituentsselected from halogen, aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl;

b. —C₂-C₆ alkenyl, optionally substituted with one or more substituentsselected from halogen, aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl; or

c. —C₂-C₆ alkynyl, optionally substituted with one or more substituentsselected from halogen, aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl;

5. R₂, wherein R₂ is selected from:

a. aryl;

b. heteroaryl;

c. substituted aryl;

d. substituted heteroaryl;

e. heterocycloalkyl; or

f. substituted heterocycloalkyl;

6. —(C₁-C₃-alkyl)-M—(C₁-C₃-alkyl)-R₂, wherein M=—O—, —NH—, —N(CH₃)—,—NHC(O)— or —S(O)_(n)—, wherein n=0, 1 or 2, and R₂ is as previouslydefined;

7. —(C₁-C₃-alkyl)-M—R₂, wherein M and R₂ are as previously defined;

8. —C(O)—V—R₃, wherein V is absent, O or S, and R₃ is H, R₁ or R₂; whereR₁ and R₂ are as previously defined; or

9. —C(O)—NR₁₁R₁₂, wherein R₁ and R₁₂ are each independently selectedfrom:

a. hydrogen;

b. —C₁-C₆-alkyl, optionally substituted with one or more substituentsselected from halogen, aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl;

c. —C₂-C₆-alkenyl, optionally substituted with one or more substituentsselected from halogen, aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl;

d. —C₂-C₆-alkynyl, optionally substituted with one or more substituentsselected from halogen, aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl; or

 in the alternative, R₁ and R₁₂ taken together with the nitrogen atom towhich they are connected form a 3- to 7-membered ring which mayoptionally contain one or more double bonds and one or moreheterofunctions selected from —O—, —NH—, —N(C₁-C₆-alkyl)—, —N(R₂)—,—S(O)_(n)—, wherein n and R₂ are as previously defined;

(b) —CH₂—CH(A)—C(B)═CH—, wherein A and B are as previously defined;

(c) —CH₂—CH(E)—CH(G)—CH₂—, wherein E and G are independently selectedfrom

1. A, wherein A is as previously defined;

2. —OH;

3. —OR^(p), wherein R^(p) is a hydroxy protecting group;

4. —O—R₉, wherein R₉ is R₁ or R₂, and wherein R₁ and R₂ are aspreviously defined;

5. —S(O)_(n)R₉, wherein n and R₉ are as previously defined;

6. —NHC(O)R₃, wherein R₃ is as previously defined;

7. —NHC(O)NR₁₁R₃, wherein R₁₁ and R₃ are as previously defined;

8. —NHS(O)₂R₉, wherein R₉ is as previously defined;

9. —NHR₁₃, wherein R₁₃ is an amino protecting group; or

10. —NR₁₁R₁₂, wherein R₁₁ and R₁₂ are as previously defined;

(d)

wherein —J— is selected from —O—; —O—C(O)—CH(R₇)—; —N(R₇)—;—O—C(O)—N(R₇)—; —O—C(O)—O—; —N(R₇)—N═N—; —C(R₇)═N—O—; or—CH(R₇)—N(R₈)—O—; wherein R₇ and R₈ are independently selected from R₃,wherein R₃ is as previously defined; or, in the alternative, —J— istaken with the two carbon atoms to which it is attached to form a cyclicmoiety selected from

a. C₃-C₁₂ cycloalkyl;

b. C₃-C₁₂ cycloalkenyl; or

c. heterocycloalkyl; or

(e) —CH₂—C(R₄)(R₅)—CH₂CH₂—, wherein R₄ and R₅ taken together with thecarbon atom to which they are attached are selected from:

1. C═O;

2. C(OR₁)₂, wherein R₁ is as previously defined;

3. C(SR₁)₂, wherein R₁ is as previously defined;

4. C(OR₁₂)(OR₁₃), where R₁₂ and R₁₃ taken together are —(CH₂)_(m)—, andwhere m is 2 or 3;

5. C(SR₁₂)(SR₁₃), where R₁₂ and R₁₃ taken together are —(CH₂)_(m)—,where m is as previously defined;

6. C═CHR₃, wherein R₃ is as previously defined;

7. C═N—O—R₃, wherein R₃ is as previously defined;

8. C═NNHR₃, wherein R₃ is as previously defined;

9. C═NNHC(O)R₃, wherein R₃ is as previously defined;

10. C═NNHC(O)NR₁₁R₃, wherein R₁₁, and R₃ are as previously defined;

11. C═NNHS(O)₂R₉, wherein R₉ is as previously defined;

12. C═NNHR₁₃, wherein R₁₃ is as previously defined; or

13. C═NR₉, wherein R₉ is as previously defined;

L is

(a) —CH₃;

(b) —CH₂CH₃;

(c) —CH(OH)CH₃;

(d) —C₁-C₆ alkyl, optionally substituted with one or more substituentsselected from aryl, substituted aryl, heteroaryl, or substitutedheteroaryl;

(e) C₂-C₆ alkenyl, optionally substituted with one or more substituentsselected from aryl, substituted aryl, heteroaryl, or substitutedheteroaryl; or

(f) —C₂-C₆ alkynyl, optionally substituted with one or more substituentsselected from aryl, substituted aryl, heteroaryl, or substitutedheteroaryl;

D is —N(Q)CH₂—, —N(R′)C(O)—, or —N═C(OR′)—, wherein R′ is R₁₁, aspreviously defined;

Q is

(a) hydrogen;

(b) —C₁C₁₂-alkyl, C₂-C₁₂-alkenyl, or C₂-C₁₂-alkynyl, all optionallysubstituted with one, two or three substituents independently selectedfrom:

1. halogen;

2. —OR₆, wherein R₆ is selected from:

a. hydrogen;

b. —C₁-C₁₂-alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, Sor N, optionally substituted with one, two, or three substituentsindependently selected from aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl;

c. aryl;

d. substituted aryl;

e. heteroaryl;

f. substituted heteroaryl;

g. heterocycloalkyl; or

h. substituted heterocycloalkyl;

3. —NR₄R₅, where R₄ and R₅ are each independently R₆, where R₆ is aspreviously defined, or in the alternative R₄ and R₅, together with theatom to which they are attached, form a heterocycloalkyl or substitutedheterocycloalkyl moiety;

4. ═N—O—R₆, where R₆ is as previously defined;

5. —R₁, where R₁ is as previously defined;

6. —C₃-C₁₂-cycloalkyl;

7. substituted —C₃-C₁₂cycloalkyl;

8. heterocycloalkyl;

9. substituted heterocycloalkyl;

10. —NHC(O)R₆, where R₆is as previously defined;

11. —NHC(O)OR₇, where R₇ is selected from:

a. C₁-C₁₂-alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, Sor N, optionally substituted with one, two, or three substituentsindependently selected from aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl;

b. aryl;

c. substituted aryl;

d. heteroaryl;

e. substituted heteroaryl;

f. heterocycloalkyl; or

g. substituted heterocycloalkyl;

12. —NHC(O)NR₄R₅, where R₄ and R₅ are as previously defined;

13. —OC(O)NR₄R₅, where R₄ and R₅ are as previously defined;

14. —OC(O)R₇, where R₇ is as previously defined;

15. —OC(O)OR₇, where R₇ is as previously defined;

16. —OC(O)NR₄R₅, where R₄ and R₅ are as previously defined,

17. —C(O)R₆, where R₆ is as previously defined,

18. —CO₂R₆, where R₆ is as previously defined, or

19. —C(O)NR₄R₅, where R₄ and R₅ are as previously defined;

X is hydrogen;

Y is

(a) hydrogen;

(b) —OH;

(c) —OR_(p), where R_(p) is as previously defined;

(d) —OR_(y), where R_(y) is R₁ and R₂ as previously defined;

(e) —OC(O)R_(y), where R_(y) is R₁ and R₂ as previously defined;

(f) —OC(O)NHR_(y), where R_(y) is R₁ and R₂ as previously defined;

(g) —S(O)_(n)R_(y), where n is previously defined and R_(y) is R₁ and R₂as previously defined;

 where R₃″ is hydrogen or methyl; R₄″ is hydrogen or R_(p), where R_(p)is as previously defined; or

(h) in the alternative, X and Y combined together are oxo;

Z is

(a) hydrogen;

(b) methyl; or

(c) halogen; and

R₂′ is hydrogen or R_(p), where R_(p), is as previously defined.

In another embodiment of the present invention there are disclosedpharmaceutical compositions comprising a therapeutically effectiveamount of a compound of the invention in combination with apharmaceutically acceptable carrier or excipient. In yet anotherembodiment of the invention are methods of treating antibacterialinfections with said pharmaceutical compositions. Suitable carriers andmethods of formulation are also disclosed.

In a further aspect of the present invention there are providedprocesses for the preparation of 6,11-4C-bicyclic 9a-azalide derivativesof formula (I).

DETAILED DESCRIPTION OF THE INVENTION

A first embodiment of the present invention is a compound of formula Ias illustrated above, or a pharmaceutically acceptable salt, ester orprodrug thereof.

Preferred subgenera of compounds of the present invention are:

A compound of the formula II:

 wherein Q, W, X, Y, Z and R₂′ are as previously defined;

A compound of formula III:

 wherein W, Q, R₂′, and R₄″ are as previously defined;

compound of formula IV:

 wherein W, O, Z and R₂′ are as previously defined;

A compound of formula V:

 wherein W, X, Y, Z, R′, and R₂′ are as previously defined;

A compound of formula VI:

 wherein W, X, Y, R′, and R₂′ are as previously defined;

A compound of formula VII:

 wherein A, B, D, X, Y, Z, and R₂ ¹′ are as previously defined;

A compound of formula VIII:

 wherein A, B, D, X, Y, Z, and R₂′ are as previously defined;

A compound of formula IX:

 wherein A, B, D, X, Y, Z, and R₂′ are as previously defined;

A compound of formula X:

 wherein D, J, X, Y, Z, and R₂′ are as previously defined; or

A compound of formula XI:

 wherein D, E, G, X, Y, Z, and R₂′ are as previously defined.

Representative compounds according to the invention are those selectedfrom:

Compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N═CH(OMe)—, X=Z=H,

L=CH₂CH₃, and R₂′=Bz;

Compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—NHCH₂—, X=Z═H,

L=CH₂CH₃, and R₂′=Bz;

Compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—NHCH₂, X=Z═H,

L=CH₂CH₃, and R₂′=H;

Compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—NHCH₂—, X=Z═H,Y=OH, L=CH₂CH₃, and R₂′=H;

Compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—NHCH₂—, X and Yare taken together with the carbon to which they are attached are C═O,L=CH₂CH₃, and R₂′=H;

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—NHC(O)—, X=Z═H,L=—CH₂CH₃,

R₂′=H;

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N(Q)CH₂—, Q=CH₃,X=Z=H, Y=OH, L=CH₂CH₃, R₂′=H;

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N(Q)CH₂—, Q=CH₃,Z=H, X and Y taken together are oxo, L=CH₂CH₃, R₂′=H;

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N(Q)CH₂—,Q=CH₂Ph, Z=X=H, Y=OH, L=CH₂CH₃, R₂′=H;

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N(Q)CH₂—,Q=CH₂Ph, Z=H, X and Y are taken together are oxo, L=CH₂CH₃, R₂′=H;

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N(Q)CH₂—,Q=CH₂(2-pyridyl), Z=X=H, Y=OH, L=CH₂CH₃, R₂′=H;

A compound of formula I, W is —CH₂CH═CHCH₂—, D=—N(Q)CH,Q=CH₂(2-pyridyl), Z=H, X and Y taken together are oxo, L=CH₂CH₃, R₂′=H;

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N(Q)CH₂—,Q=CH₂(3-quinolyl), Z=H, X and Y taken together are oxo, L=CH₂CH₃, R₂′=H;

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N(Q)CH₂—,Q=CH₂(3-quinolyl), Z=H, X and Y taken together are oxo, L=CH₂CH₃, R₂′=H;

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N(Q)CH₂—,Q=CH₂(CH═CH)Ph, Z=X=H, Y=OH, L=CH₂CH₃, R₂′=H;

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N(Q)CH₂—,Q=CH₂(CH═CH)Ph, Z=H, X and Y taken together are oxo, L=CH₂CH₃, R₂′=H;

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N(Q)CH₂—,Q=CH₂CH═CH(2-pyridyl), Z=X=H, Y=OH, L=CH₂CH₃, R₂′=H;

A compound of formula I, wherein A and B taken together with the carbonatom to which they are attached=C═CH₂, D=—N(Q)CH₂—,Q=CH₂CH═CH(2-pyridyl), Z=H, X and Y taken together are oxo, L=CH₂CH₃,R₂′=H;

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N(Q)CH₂—,Q=CH₂C≡C(3-quinolyl), Z=X=H, Y=OH, L=CH₂CH₃, R₂′=H; or

A compound of formula I, wherein W=—CH₂CH═CHCH₂—, D=—N(Q)CH₂—,Q=CH₂C≡C(3-quinolyl), Z=H, X and Y taken together are oxo, L=CH₂CH₃,R₂′=H.

A further embodiment of the present invention includes pharmaceuticalcompositions comprising any single compound delineated herein, or apharmaceutically acceptable salt, ester, or prodrug thereof, with apharmaceutically acceptable carrier or excipient.

Yet another embodiment of the present invention is a pharmaceuticalcomposition comprising a combination of two or more compounds delineatedherein, or a pharmaceutically acceptable salt, ester, or prodrugthereof, with a pharmaceutically acceptable carrier or excipient.

Yet a further embodiment of the present invention is a pharmaceuticalcomposition comprising any single compound delineated herein incombination with one or more antibiotics known in the art, or apharmaceutically acceptable salt, ester, or prodrug thereof, with apharmaceutically acceptable carrier or excipient.

In addition, the present invention contemplates processes of making anycompound delineated herein via any synthetic method delineated herein.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The terms “C₁-C₃ alkyl,” “C₁-C₆ alkyl,” or “C₁-C₁₂ alkyl,” as usedherein, refer to saturated, straight- or branched-chain hydrocarbonradicals containing between one and three, one and twelve, or one andsix carbon atoms, respectively. Examples of C₁-C₃ alkyl radicals includemethyl, ethyl, propyl and isopropyl radicals; examples of C₁-C₆ alkylradicals include, but are not limited to, methyl, ethyl, propyl,isopropyl, n-butyl, tert-butyl, neopentyl and n-hexyl radicals; andexamples of C₁-C₁₂ alkyl radicals include, but are not limited to,ethyl, propyl, isopropyl, n-hexyl, octyl, decyl, dodecyl radicals.

The term “substituted alkyl,” as used herein, refers to a “C₂-C₁₂ alkyl”or “C₁-C₆ alkyl” group as previously defined, substituted by independentreplacement or one, two, or three of the hydrogen atoms thereon withsubstituents including, but not limited to, —F, —Cl, —Br, —I, —OH,protected hydroxy, —NO₂, —CN, —C₁-C₁₂-alkyl optionally substituted withhalogen, C₂-C₁₂-alkenyl optionally substituted with halogen,—C₂-C₁₂-alkynyl optionally substituted with halogen, —NH₂, protectedamino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkenyl,—NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl,—O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl,—O-heteroaroayl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₃-C₁₂-cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl,—CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂—aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O) NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C_(1-C) ₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)—heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,-methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl,—S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl, —S—C₃-C₁₂-cycloalkyl, —S-aryl,—S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

The terms “C₂-C₁₂ alkenyl” or “C₂-C₆ alkenyl,” as used herein, denote amonovalent group derived from a hydrocarbon moiety containing from twoto twelve or two to six carbon atoms having at least one carbon-carbondouble bond by the removal of a single hydrogen atom. Alkenyl groupsinclude, but are not limited to, for example, ethenyl, propenyl,butenyl, 1-methyl-2-buten-1-yl, and the like.

The term “substituted alkenyl,” as used herein, refers to a “C₂-C₂alkenyl” or “C₂-C₆ alkenyl” group as previously defined, substituted byindependent replacement or one, two, or three of the hydrogen atomsthereon with substituents including, but not limited to, —F, —Cl, —Br,—I, —OH, protected hydroxy, —NO₂, —CN, —C₁-C₁₂-alkyl optionallysubstituted with halogen, C₂-C₁₂-alkenyl optionally substituted withhalogen, —C₂-C₁₂-alkynyl optionally substituted with halogen, —NH₂,protected amino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl,—NH—C₂-C₁₂-alkenyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl,—NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino,—O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl, —O—-C₂-C₁₂-alkenyl,—O—-C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl,—OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₃-C₁₂-Cycloalkyl, —OCO₂-aryl, —OCO₂-heteroaryl,—OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S) NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NHC₂—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂-C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,-methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl,—S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl, —S—C₃-C₁₂-cycloalkyl, —S-aryl,—S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

The terms “C₂-C₁₂ alkynyl” or “C₂-C₆ alkynyl,” as used herein, denote amonovalent group derived from a hydrocarbon moiety containing from twoto twelve or two to six carbon atoms having at least one carbon-carbontriple bond by the removal of a single hydrogen atom. Representativealkynyl groups include, but are not limited to, for example, ethynyl,1-propynyl, 1-butynyl, and the like.

The term “substituted alkynyl,” as used herein, refers to a “C₂-C₁₂alkynyl” or “C₂-C₆ alkynyl” group as previously defined, substituted byindependent replacement or one, two, or three of the hydrogen atomsthereon with substituents including, but not limited to, —F, —Cl, —Br,—I, —OH, protected hydroxy, —NO₂, —CN, —C₁-C₁₂-alkyl optionallysubstituted with halogen, C₂-C₁₂-alkenyl optionally substituted withhalogen, —C₂-C₁₂-alkynyl optionally substituted with halogen, —NH₂,protected amino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl,—NH—C₂-C₁₂-alkenyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl,—NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino,—O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl,—OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂, -aryl, —OCO₂-heteroaryl,—OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃—C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,-methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl,—S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl, —S—C₃-C₁₂-cycloalkyl, —S-aryl,—S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

The term “C₁-C₆ alkoxy,” as used herein, refers to a C₁-C₆ alkyl group,as previously defined, attached to the parent molecular moiety throughan oxygen atom. Examples of C₁-C₆-alkoxy include, but are not limitedto, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy,neopentoxy and n-hexoxy.

The terms “halo” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

The term “aryl,” as used herein, refers to a mono- or bicycliccarbocyclic ring system having one or two aromatic rings including, butnot limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyland the like.

The term “substituted aryl,” as used herein, refers to an aryl group, aspreviously defined, substituted by independent replacement or one, two,or three of the hydrogen atoms thereon with substituents including, butnot limited to, —F, —Cl, —Br, —I, —OH, protected hydroxy, —NO₂, —CN,—C₁-C₁₂-alkyl optionally substituted with halogen, C₂-C₁₂-alkenyloptionally substituted with halogen, —C₂-C₁₂-alkynyl optionallysubstituted with halogen, —NH₂, protected amino, —NH—C₁-C₁₂-alkyl,—NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkenyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl,—NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino,-diheteroarylamino, —O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl,—O—C₂-C₁₂-alkenyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl,—O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl,—C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl,—OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl, —OCO₂-heteroaryl,—OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,-NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃—C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,-methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl,—S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl, —S—C₃-C₁₂-cycloalkyl, —S-aryl,—S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

The term “arylalkyl,” as used herein, refers to a C₁-C₃ alkyl or C₁-C₆alkyl residue attached to an aryl ring. Examples include, but are notlimited to, benzyl, phenethyl and the like.

The term “substituted arylalkyl,” as used herein, refers to an arylalkylgroup, as previously defined, substituted by independent replacement orone, two, or three of the hydrogen atoms thereon with substituentsincluding, but not limited to, but not limited to, —F, —Cl, —Br, —I,—OH, protected hydroxy, —NO₂, —CN, —C₁-C₁₂-alkyl optionally substitutedwith halogen, C₂-C₁₂-alkenyl optionally substituted with halogen,—C₂-C₁₂-alkynyl optionally substituted with halogen, —NH₂, protectedamino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkenyl,—NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl,—O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₃-C₁₂-cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl,—CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl-SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,-methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl,—S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl, —S—C₃-C₁₂-cycloalkyl, —S-aryl,—S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

The term “heteroaryl,” as used herein, refers to a mono-, bi-, ortri-cyclic aromatic radical or ring having from five to ten ring atomsof which one ring atom is selected from S, O and N; zero, one or tworing atoms are additional heteroatoms independently selected from S, Oand N; and the remaining ring atoms are carbon, wherein any N or Scontained within the ring may be optionally oxidized. Heteroarylincludes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl,pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and thelike.

The term “substituted heteroaryl,” as used herein, refers to aheteroaryl group as previously defined, substituted by independentreplacement or one, two, or three of the hydrogen atoms thereon withsubstituents including, but not limited to, —F, —Cl, —Br, —I, —OH,protected hydroxy, —NO₂, —CN, —C₁-C₁₂-alkyl optionally substituted withhalogen, C₂-C₁₂-alkenyl optionally substituted with halogen,—C₂-C₁₂-alkynyl optionally substituted with halogen, —NH₂, protectedamino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkenyl,—NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl,—O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₃-C₁₂-cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl,—CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₃-C₁₂-cycloalkyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂,—OCONH—C₁-C₁₂-alkyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl,—OCONH—C₃-C₁₂-cycloalkyl, —OCONH-aryl, —OCONH-heteroaryl,—OCONH-heterocycloalkyl, —NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl,—NHC(O)-heteroaryl, —NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂-C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl,—NHCO₂-aryl, —NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,—NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl-SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,-methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl,—S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl, —S—C₃-C₁₂-cycloalkyl, —S-aryl,—S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

The term “C₃-C₁₂-cycloalkyl,” as used herein, denotes a monovalent groupderived from a monocyclic or bicyclic saturated carbocyclic ringcompound by the removal of a single hydrogen atom. Examples include, butnot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,bicyclo[2.2.1] heptyl, and bicyclo[2.2.2] octyl.

The term “substituted C₃-C₁₂-cycloalkyl,” as used herein, refers to aC₃-C₁₂-cycloalkyl group as previously defined, substituted byindependent replacement or one, two, or three of the hydrogen atomsthereon with substituents including, but not limited to, —F, —Cl, —Br,—I, —OH, protected hydroxy, —NO₂, —CN, —C₁-C₁₂-alkyl optionallysubstituted with halogen, C₂-C₁₂-alkenyl optionally substituted withhalogen, —C₂-C₁₂-alkynyl optionally substituted with halogen, —NH₂,protected amino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl,—NH—C₂-C₁₂-alkenyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl,—NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino,—O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl,—OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₃-C₁₂-alkenyl,—OCO₂—C₃-C₁₂-cycloalkyl, aryl, —OCO₂-heteroaryl, —OCO₂-heterocycloalkyl,—OCONH₂, —OCONH—C₁-C₁₂-alkyl, —OCONH—C₂-C₁₂-alkenyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl, —OCONH-aryl,—OCONH-heteroaryl, —OCONH-heterocycloalkyl, —NHC(O)—C₁-C₁₂-alkyl,—NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O) NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S) NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₁-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂cycloalkyl,-methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl,—S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl, —S—C₃-C₁₂-cycloalkyl, —S-aryl,—S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

The term “C₃-C₁₂-cycloalkenyl,” as used herein, denotes a monocyclic orbicyclic carbocyclic ring compound where each 5-membered ring has 0 to 1double bonds and each 6-membered ring has 0 to 2 double bonds. Examplesinclude, but not limited to, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]heptenyl, and bicyclo[2.2.2] octenyl.

The term “heterocycloalkyl,” as used herein, refers to a non-aromatic5-, 6-or 7-membered ring or a bi-or tri-cyclic group fused system, where(i) each ring contains between one and three heteroatoms independentlyselected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds,(iii) the nitrogen and sulfur heteroatoms may optionally be oxidized,(iv) the nitrogen heteroatom may optionally be quaternized, and (iv) anyof the above rings may be fused to a benzene ring. Representativeheterocycloalkyl groups include, but are not limited to, [1,3]dioxolane,pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

The term “substituted heterocycloalkyl,” as used herein, refers to aheterocycloalkyl group, as previously defined, substituted byindependent replacement or one, two, or three of the hydrogen atomsthereon with substituents including, but not limited to, —F, —Cl, —Br,—I, —OH, protected hydroxy, —NO₂, —CN, —C₁-C₁₂-alkyl optionallysubstituted with halogen, C₂-C₁₂-alkenyl optionally substituted withhalogen, —C₂-C₁₂-alkynyl optionally substituted with halogen, —NH₂,protected amino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl,—NH—C₂-C₁₂-alkenyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl,—NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino,—O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl,—O—C₃-C₁₂-cycloalkyl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl, —CON H—C₃-C₁₂-cycloalkyl,—CONH-aryl, CONH-heteroaryl, —CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl,—OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₃-C₁₂-cycloalkyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂,—OCONH—C₁-C₁₂-alkyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl,—OCONH—C₃-C₁₂-cycloalkyl, —OCONH-aryl, —OCONH-heteroaryl,—OCONH-heterocycloalkyl, —NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₃-C₁₂clycloalkyl, —NHC(O)-aryl,—NHC(O)-heteroaryl, —NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl,—NHCO₂-aryl, —NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,-methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl,—S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl, —S—C₃-C₁₂-cycloalkyl, —S-aryl,—S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

The term “heteroarylalkyl,” as used herein, refers to a C₁-C₃ alkyl orC₁-C₆ alkyl residue residue attached to a heteroaryl ring. Examplesinclude, but are not limited to, pyridinylmethyl, pyrimidinylethyl andthe like.

The term “substituted heteroarylalkyl,” as used herein, refers to aheteroarylalkyl group, as previously defined, substituted by independentreplacement or one, two, or three of the hydrogen atoms thereon withsubstituents including, but not limited to, —F, —Cl, —Br, —I, —OH,protected hydroxy, —NO₂, —CN, C₁-C₁₂-alkyl optionally substituted withhalogen, C₂-C₁₂-alkenyl optionally substituted with halogen,—C₂-C₁₂-alkynyl optionally substituted with halogen, —NH₂, protectedamino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkenyl,—NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl,—O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₃-C₁₂-cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₂-alkenyl, —OCONH—C₂-C₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl-SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,-methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl,—S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl, —S—C₃-C₁₂-cycloalkyl, —S-aryl,—S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

The term “C₁-C₆ alkoxy,” as used herein, refers to a C₁-C₆ alkyl group,as previously defined, attached to the parent molecular moiety throughan oxygen atom. Examples of C₁-C₆-alkoxy include, but are not limitedto, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy,neopentoxy and n-hexoxy.

The term “C₁-C₃-alkyl-amino,” as used herein, refers to one or twoC₁-C₃-alkyl groups, as previously defined, attached to the parentmolecular moiety through a nitrogen atom. Examples of C₁-C₃-alkyl-aminoinclude, but are not limited to, methylamino, dimethylamino, ethylamino,diethylamino, and propylamino.

The term “alkylamino” refers to a group having the structure —NH(C₁-C₁₂alkyl) where C₁-C₁₂ alkyl is as previously defined.

The term “dialkylamino” refers to a group having the structure —N(C₁-C₁₂alkyl) (C₁-C₁₂ alkyl), where C₁-C₁₂ alkyl is as previously defined.Examples of dialkylamino are, but not limited to, dimethylamino,diethylamino, methylethylamino, piperidino, and the like.

The term “alkoxycarbonyl” represents an ester group, i.e., an alkoxygroup, attached to the parent molecular moiety through a carbonyl groupsuch as methoxycarbonyl, ethoxycarbonyl, and the like.

The term “carboxaldehyde,” as used herein, refers to a group of formula—CHO.

The term “carboxy,” as used herein, refers to a group of formula —COOH.

The term “carboxamide,” as used herein, refers to a group of formula—C(O)NH(C₁-C₁₂ alkyl) or —C(O)N(C₁-C₁₂ alkyl)(C₁-C₁₂ alkyl), —C(O)NH₂,and the like.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York(1999). Examples of hydroxy protecting groups include, but are notlimited to, methylthiomethyl, tert-butyl-dimethylsilyl,tert-butyldiphenylsilyl, acyl substituted with an aromatic group and thelike.

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the aredescribed generally in T. H. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).Examples of amino protecting groups include, but are not limited to,t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and thelike.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al., Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The term “protogenic organic solvent,” as used herein, refers to asolvent that tends to provide protons, such as an alcohol, for example,methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and thelike. Such solvents are well known to those skilled in the art, and itwill be obvious to those skilled in the art that individual solvents ormixtures thereof may be preferred for specific compounds and reactionconditions, depending upon such factors as the solubility of reagents,reactivity of reagents and preferred temperature ranges, for example.Further discussions of protogenic solvents may be found in organicchemistry textbooks or in specialized monographs, for example: OrganicSolvents Physical Properties and Methods of Purification, 4th ed.,edited by John A. Riddick et al., Vol. II, in the Techniques ofChemistry Series, John Wiley & Sons, NY, 1986.

“An effective amount,” as used herein, refers to an amount of a compoundwhich confers a therapeutic effect on the treated subject. Thetherapeutic effect may be objective (i.e., measurable by some test ormarker) or subjective (i.e., subject gives an indication of or feels aneffect). An effective amount of the compound described above may rangefrom about 0.1 mg/Kg to about 500 mg/Kg, preferably from about 1 toabout 50 mg/Kg. Effective doses will also vary depending on route ofadministration, as well as the possibility of co-usage with otheragents.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The term “subject” as used herein refers to an animal. Preferably theanimal is a mammal. More preferably the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. The configuration ofany carbon-carbon double bond appearing herein is selected forconvenience only and is not intended to designate a particularconfiguration unless the text so states; thus a carbon-carbon doublebond or carbon-heteroatom double bond depicted arbitrarily herein astrans may be cis, trans, or a mixture of the two in any proportion.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu du ring the final isolation and purification of the compounds ofthe invention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable include,but are not limited to, nontoxic acid addition salts are salts of anamino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesutfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesuffonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quatemary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the compounds of this invention, including the compoundsof formulae described herein, are defined to include pharmaceuticallyacceptable derivatives or prodrugs thereof. A “pharmaceuticallyacceptable derivative or prodrug” means any pharmaceutically acceptablesalt, ester, salt of an ester, or other derivative of a compound of thisinvention which, upon administration to a recipient, is capable ofproviding (directly or indirectly) a compound of this invention.

When the compositions of this invention comprise a combination of acompound of the formulae described herein and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 1 to 100%, andmore preferably between about 5 to 95% of the dosage normallyadministered in a monotherapy regimen. The additional agents may beadministered separately, as part of a multiple dose regimen, from thecompounds of this invention. Alternatively, those agents may be part ofa single dosage form, mixed together with the compounds of thisinvention in a single composition.

As used herein, unless otherwise indicated, the term “bacterialinfection(s)” or “protozoa infections”; includes, but is not limited to,bacterial infections and protozoa infections that occur in mammals, fishand birds as well as disorders related to bacterial infections andprotozoa infections that may be treated or prevented by administeringantibiotics such as the compounds of the present invention. Suchbacterial infections and protozoa infections and disorders related tosuch infections include, but are not limited to, the following:pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, andmastoiditis related to infection by Streptococcus pneumoniae,Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, orPeptostreptococcus spp. Pseudomonas spp.; pharynigitis, rheumatic fever,and glomerulonephritis related to infection by Streptococcus pyogenes,Groups C and G streptococci, Clostridium diptheriae, or Actinobacillushaemolyticum; respiratory tract infections related to infection byMycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae,Haemophilus influenzae, or Chlamydia pneumoniae; uncomplicated skin andsoft tissue infections, abscesses and osteomyelitis, and puerperal feverrelated to infection by Staphylococcus aureus, coagulase-positivestaphylococci (i.e., S. epidermidis, S. hemolyticus, etc.), S. pyogenes,S. agalactiae, Streptococcal groups C-F (minute-colony streptococci),viridans streptococci, Corynebacterium spp., Clostridium spp., orBartonella henselae; uncomplicated acute urinary tract infectionsrelated to infection by S. saprophyticus or Enterococcus spp.;urethritis and cervicitis; and sexually transmitted diseases related toinfection by Chlamydia trachomatis, Haemophilus ducreyi, Treponemapallidum, Ureaplasma urealyticum, or Nesseria gonorrheae; toxin diseasesrelated to infection by S. aureus (food poisoning and Toxic shocksyndrome), or Groups A, S, and C streptococci; ulcers related toinfection by Helicobacter pylori; systemic febrile syndromes related toinfection by Borrelia recurrentis; Lyme disease related to infection byBorrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitisrelated to infection by C. trachomatis, N. gonorrhoeae, S. aureus, S.pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.; disseminatedMycobacterium avium complex (MAC) disease related to infection byMycobacterium avium, or Mycobacterium intracellulare; gastroenteritisrelated to infection by Campylobacter jejuni; intestinal protozoarelated to infection by Cryptosporidium spp. odontogenic infectionrelated to infection by viridans streptococci; persistent cough relatedto infection by Bordetella pertussis; gas gangrene related to infectionby Clostridium perfringens or Bacteroides spp.; Skin infection by S.aureus, Propionibacterium acne; atherosclerosis related to infection byHelicobacter pylori or Chlamydia pneumoniae; or the like.

Bacterial infections and protozoa infections and disorders related tosuch infections that may be treated or prevented in animals include, butare not limited to, the following: bovine respiratory disease related toinfection by P. haemolytica., P. multocida, Mycoplasma bovis, orBordetella spp.; cow enteric disease related to infection by E. coli orprotozoa (i.e., coccidia, cryptosporidia, etc.), dairy cow mastitisrelated to infection by S. aureus, S. uberis, S. agalactiae, S.dysgalactiae, Klebsiella spp., Corynebacterium, or Enterococcus spp.;swine respiratory disease related to infection by A. pleuropneumoniae.,P. multocida, or Mycoplasma spp.; swine enteric disease related toinfection by E. coli, Lawsonia intracellularis, Salmonella spp., orSerpulina hyodyisinteriae; cow footrot related to infection byFusobacterium spp.; cow metritis related to infection by E. coli; cowhairy warts related to Infection by Fusobacterium necrophorum orBacteroides nodosus; cow pink-eye related to infection by Moraxellabovis, cow premature abortion related to infection by protozoa (i.e.neosporium); urinary tract infection in dogs and cats related toinfection by E. coli; skin and soft tissue infections in dogs and catsrelated to infection by S. epidermidis, S. intermedius, coagulase neg.Staphylococcus or P. multocida; and dental or mouth infections in dogsand oats related to infection by Alcaligenes spp., Bacteroides spp.,Clostridium spp., Enterobacter spp., Eubacterium spp.,Peptostreptococcus spp., Porphfyromonas spp., Campylobacter spp.,Actinomyces spp., Erysipelothrix spp., Rhodococcus spp., Trypanosomaspp., Plasodium spp., Babesia spp., Toxoplasma spp., Pneumocystis spp.,Leishmania spp., and Trichomonas spp. or Prevotella spp. Other bacterialinfections and protozoa infections and disorders related to suchinfections that may be treated or prevented in accord with the method ofthe present invention are referred to in J. P. Sanford at al., “TheSanford Guide To Antimicrobial Therapy,” 26th Edition, (AntimicrobialTherapy, Inc., 1996).

Antibacterial Activity

Susceptibility tests can be used to quantitatively measure the in vitroactivity of an antimicrobial agent against a given bacterial isolate.Compounds were tested for in vitro antibacterial activity by amicro-dilution method. Minimal Inhibitory Concentration (MIC) wasdetermined in 96 well microtiter plates utilizing the appropriateMueller Hinton Broth medium (CAMHB) for the observed bacterial isolates.Antimicrobial agents were serially diluted (2-fold) in DMSO to produce aconcentration range from about 64 μg/ml to about 0.03 μg/ml. The dilutedcompounds (2 μl/well) were then transferred into sterile, uninoculatedCAMHB (0.2 mL) by use of a 96 fixed tip-pipetting station. The inoculumfor each bacterial strain was standardized to 5×10⁵ CFU/mL by opticalcomparison to a 0.5 McFarland turbidity standard. The plates wereinoculated with 10 μl/well of adjusted bacterial inoculum. The 96 wellplates were covered and incubated at 35+/−2° C. for 24 hours in ambientair environment. Following incubation, plate wells were visuallyexamined by Optical Density measurement for the presence of growth(turbidity). The lowest concentration of an antimicrobial agent at whichno visible growth occurs was defined as the MIC. The compounds of theinvention generally demonstrated an MIC in the range from about 64 μg/mlto about 0.03 μg/ml.

All in vitro testing follows the guidelines described in the ApprovedStandards M7-A4 protocol, published by the National Committee forClinical Laboratory Standards (NCCLS).

Pharmaceutical Compositions.

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrastemal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringers solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono-or diglyceddes. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearale, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

According to the methods of treatment of the present invention,bacterial infections are treated or prevented in a patient such as ahuman or other animals by administering to the patient a therapeuticallyeffective amount of a compound of the invention, in such amounts and forsuch time as is necessary to achieve the desired result.

By a “therapeutically effective amount” of a compound of the inventionis meant a sufficient amount of the compound to treat or preventbacterial infections, at a reasonable benefit/risk ratio applicable toany medical treatment. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific therapeutically effective dose level forany particular patient will depend upon a variety of factors includingthe disorder being treated and the severity of the disorder; theactivity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or contemporaneously with thespecific compound employed; and like factors well known in the medicalarts.

The total daily dose of the compounds of this invention administered toa human or other animal in single or in divided doses can be in amounts,for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1to 25 mg/kg body weight. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. In general,treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

The compounds of the formulae described herein can, for example, beadministered by injection, intravenously, intraarterially, subdermally,intraperitoneally, intramuscularly, or subcutaneously; or orally,buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.5 toabout 100 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with the carrier materials to produce a singledosage form will vary depending upon the host treated and the particularmode of administration. A typical preparation will contain from about 5%to about 95% active compound (w/w). Alternatively, such preparations maycontain from about 20% to about 80% active compound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

The pharmaceutical compositions of this invention can be administeredorally to fish by blending said pharmaceutical compositions into fishfeed or said pharmaceutical compositions may be dissolved in water inwhich infected fish are placed, a method commonly referred to as amedicated bath. The dosage for the treatment of fish differs dependingupon the purpose of administration (prevention or cure of disease) andtype of administration, size and extent of infection of the fish to betreated. Generally, a dosage of 5-1000 mg, preferably 20-100 mg, per kgof body weight of fish may be administered per day, either at one timeor divided into several times. It will be recognized that theabove-specified dosage is only a general range which may be reduced orincreased depending upon the age, body weight, condition of disease,etc. of the fish.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one with ordinary skill inthe art. All publications, patents, published patent applications, andother references mentioned herein are hereby incorporated by referencein their entirety.

Abbreviations

Abbreviations which may appear in the following synthetic schemes andexamples are:

Ac for acetyl;

AIBN for azobisisobutyronitrile;

9-BBN for 9-borabicyclo[3.3.13]nonane;

Boc for tert-butoxycarbonyl;

Bu₃SnH for tributyltin hydride;

Bz for benzyl;

CDI for carbonyidiimidazole;

dba for dibenzylidene acetone;

DBU for 1,8-diazabicyclo[5.4.0]undec-7ene;

DEAD for diethylazodicarboxylate;

Dess-Martin periodinane for1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one;

DMAP for dimethylaminopyridine;

DMF for dimethyl formamide;

DMSO for dimethyl sulfoxide;

DPPA for diphenylphosphoryl azide;

dppb for diphenylphosphino butane;

EtOAc for ethyl acetate;

iPrOH for isopropanol;

NaHMDS for sodium bis(trimethylsilyl)amide;

NMO for N-methylmorpholine N-oxide;

MeOH for methanol;

MOM for methoxymethyl;

PDC for pyridinium dichromate;

Ph for phenyl;

POPd for dihydrogen dichlorobis(di-tert-butylphosphino)palladium(II);

TBAHS for tetrabutyl ammonium hydrogen sulfate;

TBS for tert-butyl dimethylsilyl;

TEA for triethylamine;

THF for tetrahydrofuran;

TMS for trimethyl silyl;

TPAP for tetra-n-propyl ammonium perruthenate;

TPP for triphenylphosphine; and

Tris for Tris(hydroxymethyl)aminomethane.

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared.

A preferred intermediate for the preparation of compounds represented byformula I is a compound represented by the formula Ia:

wherein

1) R⁸ is

a. hydrogen,

b. —CH₂O(CH₂)₂OCH₃,

c. —CH₂O(CH₂O)_(n)CH₃, where n is as previously defined;

d. —C₁-C₁₂ alkyl, optionally substituted with one or more substituentsselected from aryl, substituted aryl, heteroaryl and substitutedheteroaryl;

e. —C₃-C₁₂ cycloalkyl;

f. —C(O)—C₁-C₁₂ alkyl;

g. —C(O)—C₃-C₁₂ cycloalkyl;

h. —C(O)—R₁, where R₁ is as previously defined; or

i. —Si(R_(a))(R_(b))(R_(c)), wherein R_(a), R_(b) and R_(c) are eachindependently selected from C₁-C₁₂ alkyl, aryl and substituted aryl; and

2) L, R₂′, and R₄″ are as previously defined.

A second preferred intermediate for the preparation of compoundsrepresented by formula I is a compound represented by the formula Ib

wherein L and R₂′ are as previously defined.

A process of the invention, as illustrated in Scheme 1, involvespreparing a compound of formula (1-4) by reacting a compound of formula(1-2) with a suitable alkylating agent.

In accordance with Scheme 1, the 9-keto group of erythromycins can beinitially converted into an oxime by methods described in U.S. Pat. No.4,990,602, followed by the protection of the 2′- and 4″-hydroxyl and, ifdesired, the oxime groups of the erythromycin derivatives to obtain thecompounds of formula (1-2).

The preparation of protected erythromycins is also described in U.S.Pat. Nos. 4,990,602; 4,331,803; 4,680,386, 4,670,549, European PatentApplication No. EP 260,938.

The 2′- and 4″-hydroxyl groups are protected by reaction with suitablehydroxyl protecting reagents in an aprotic solvent. Typical hydroxylprotecting reagents include, but are not limited to, acetylating agents,silylating agents, acid anhydrides, and the like. Examples of hydroxylprotecting reagents are, for example, acetyl chloride, acetic anhydride,benzoyl chloride, benzoic anhydride, benzyl chloroformate,hexamethyldisilazane, and trialkylsilyl chlorides.

Examples of aprotic solvents are dichloromethane, chloroform,tetrahydrofuran, N-methylpyrrolidinone, dimethylsulfoxide,N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphorictriamide, a mixture thereof or a mixture of one of these solvents withether, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-dichloroethane,acetonitrile, ethyl acetate, acetone and the like. Aprotic solvents donot adversely affect the reaction. Preferably, the solvent is selectedfrom dichloromethane, chloroform, N,N-dimethylformamide,tetrahydrofuran, N-methylpyrrolidinone or mixtures thereof. A morethorough discussion of solvents and conditions for protecting thehydroxyl group can be found in T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3^(rd) ed., John Wiley & Son,Inc, 1999.

Protection of 2′- and 4″-hydroxyl groups may be accomplishedsequentially or simultaneously to provide compound (1-2) where R₂′and/or R₄″ can be, for example, acetyl, benzoyl, trimethylsilyl, and thelike. Preferred protecting groups include acetyl, benzoyl, andtrimethylsilyl. A particularly preferred group for protecting thehydroxyl and oxime groups is the benzyl protecting group, whereinR₂′=R₄″=R₈=Bz.

Benzoylation of the R₂′ and R₄″ and R₈ hydroxy groups can be achievedthrough treatment with benzoic anhydride in THF in the presence oftriethylamine and DMAP.

The erythromycin derivative of formula (1-2) is then reacted with analkylating agent of the formula:

 R₁₂—OC(O)O—CH₂C(A)═C(B)CH₂—OC(O)—OR₁₂  (1-3),

wherein R₁₂ is C₁-C₁₂-alkyl and R₁₁ is as previously defined.

Most palladium (0) catalysts are expected to work in this process. Somepalladium (II) catalysts, such as palladium (II) acetate, which isconverted into a palladium (0) species in-situ by the actions of aphosphine, will work as well. See, for example, Beller et al. Angew.Chem. Int. Ed. Engl., 1995, 34 (17), 1848. The palladium catalyst can beselected from, but not limited to, palladium (II) acetate,tetrakis(triphenylphospine)palladium (0),tris(dibenzylideneacetone)dipalladium,tetradibenzylideneacetone)dipalladium and the like. Palladium on carbonand palladium (II) halide catalysts are less preferred than otherpalladium catalysts for this process. Suitable phosphines include, butare not limited to, triphenylphosphine, bis(diphenylphosphino)methane,bis(diphenylphosphino)ethane, bis(diphenylphosphino)propane,1,4-bis(diphenylphosphino)butane, bis(diphenylphosphino)pentane, andtri-o-tolyl-phosphine, and the like. The reaction is carried out inanaprotic solvent, preferably at elevated temperature, preferably at orabove 50° C. Suitable aprotic solvents include, but are not limited to,tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide,N-methyl-2-pyrrolidone, hexamethylphosphoric triamide,1,2-dimethoxyethane, methyl-tert-butyl ether, heptane, acetonitrile,isopropyl acetate and ethyl acetate. The most preferred solvents aretetrahydrofuran or toluene.

Generally, the alkylating agents have the formula (1-3) as previouslydescribed. The preferred alkylating agents are those wherein R₁₂ istert-butyl, isopropyl or isobutyl. The alkylating reagents are preparedby reaction of a diol with a wide variety of compounds for incorporatingthe di-carbonate moiety. The compounds include, but are not limited to,tert-butyl chloroformate, di-tert-butyl dicarbonate, and1-(tert-butoxycarbonyl)imidazole and the reaction is carried out in thepresence of an organic or an inorganic base. The temperature of thereaction varies from about −30° C. to approximately 30° C. Preferablythe alkylating reagent is di-tert-butyl dicarbonate.

An alternative method of converting the alcohol into the carbonateinvolves treating the alcohol with phosgene or triphosgene to preparethe chloroformate derivative of the diol. The di-chloroformatederivative is then converted into the di-carbonate by the methodsdescribed in Cotarca, L., Delogu, P., Nardelli, A., Sunijic, V,Synthesis, 1996, 553. The reaction can be carried out in a variety oforganic solvents such as dichloromethane, toluene, diethyl ether, ethylacetate and chloroform in the presence of a base. Examples of suitablebases include, but are not limited to, sodium hydroxide, potassiumhydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate,ammonium carbonate, DMAP, pyridine, triethylamine and the like. Thetemperature can vary from 0° C. to approximately 60° C. The reactionruns to completion in 3 to 5 hours.

Another process of the invention involves the removal of the cladinosemoiety of the compounds of formula 1. The cladinose moiety of themacrolide compound (1-4) is removed either by mild acid hydrolysis or byenzymatic hydrolysis to afford compounds of formula (2-1) in Scheme 2.Representative acids include, but are not limited to, dilutehydrochloric acid, sulfuric acid, perchloric acid, chloroacetic acid,dichloroacetic acid or trifluoroacetic acid. Suitable solvents for thereaction include, but are not limited to, methanol, ethanol,isopropanol, butanol, water and mixtures there of. Reaction times aretypically 0.5 to 24 hours. The reaction temperature is preferably 0 to80° C.

The compound of formula (2-1) where R₂′ is Ac can be converted into thecompound of formula (3-1) and (3-3) by Beckmann rearrangement. Thus, thecompound of formula (2-1) is treated with oxime activating agents andsubsequently quenched by addition of alcohol of formula (R′OH, where R′is as previously defined) to provide the compounds of formula (3-1).Representative oxime activating agents include, but are not limited to,sulfonic anhydrides and sulfonyl halides such as p-toluenesulfonicanhydride, methanesulfonic anhydride, p-toluenesulfonyl chloride,methanesulfonyl chloride, p-bromosulfonyl chloride, optionally in thepresence of a base such as, but not limited to, pyridine, triethylamine, diisopropylethyl amine, NaHCO₃, Na₂CO₃, KHCO₃ and K₂CO₃. Forfurther details concerning the Beckmann rearrangement see L. G.Donamima, W. Z. Heldt, Org. React. 11, 1-156 (1960); R. E. Gawley, ibid.35, 1-420 (1988); C. G. McCarty in The Chemistry of the Carbon-NitrogenDouble Bond, S. Patai, Ed. (Interscience, New York, 1970) pp 408-439; J.R. Hauske, Comp. Org. Syn. 1, 98-100 (1991); K. Maruoka, H. Yamamoto,ibid. 6, 763-775; D. Craig, ibid. 7, 689-702.

Reduction of compounds of formula (3-1) to compounds of formula (3-2)can be achieved by treatment of the former with reducing agentsincluding, but not limited to, borane in THF, borane dimethylsulfide,sodium cyanoborohydride, sodium borohydride optionally in the presenceof an acid such as TiCl₄, COCl₂, AICl₃, methanesulfonic acid, or aceticacid. Solvents which are applicable include, but are not limited to,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, isopropanol, ethanol,butanol, acetonitrile, diethyl ether, dichloromethane, water andmixtures thereof. The reaction temperature is −78° C. to 30° C. In aparticularly preferred embodiment, compounds of formula (2-1) aretreated with p-toluenesulfonic anhydride and triethylamine in methylenechloride and subsequently quenched with methanol to provide compounds offormula (3-1). Compounds of formula (3-1) are then treated with NaBH₄ inmethanol to provide the compounds of formula (3-2). The compounds offormula (3-3) were synthesized via treatment of compounds of formula(2-1) with p-toluenesulfonyl chloride and NaHCO₃ in acetone and water.

Compounds of formula (3-2) can be converted to compounds of formula(4-1) by treatment of the former with alkylating agent Q-X₁, wherein X₁is a halo leaving group, in the presence of base. An alternative meansof converting compounds of formula (3-2) to compounds of formula (4-1)is treatment of the compounds of formula (3-2) with an aldehyde Q—CHO inthe presence of acetic acid and excess NaCNBH₃ to provide compounds offormula (4-1) where a is —CH₂R₂, wherein R₂ is as previously defined.Examples of solvents include, but are not limited to, acetonitrile,diethylether, dichloromethane, chloroform, ethyl acetate, THF, dioxaneor mixtures thereof. The reaction generally proceeds at from −20° C. to80° C. for 30 minutes to 18 hours. In a particularly preferredembodiment, Q—CHO is reacted with (3-2) in chloroform at 80° C.

Conversion of compounds of formula (4-1) to compounds of formula (5-1)can be accomplished by oxidation of the 3-hydroxy group to a 3-oxo groupusing Dess-Martin periodinane (for further details concerning theDess-Martin oxidation see D. B. Dess, J. C. Martin, J. Org. Chem. 48,4155 (1983)), a Corey-Kim reaction withN-chlorosuccinimide-dimethylsulfide (for further details concerning theCorey-Kim oxidation reaction see E. J. Corey, C. U. Kim, J. Am. Chem.Soc. 94, 7586 (1972)), or a Moffat oxidation with a carbodiimide-DMSOcomplex in the presence of pyridinium trifluoroacetate, TPAP, PDC, andthe like (for further details concerning the Moffat oxidation see J. G.Moffatt, “Sulfoxide-Carbodiimide and Related Oxidations” in Oxidationvol. 2, R. L. Augustine, D. J. Trecker, Eds. (Dekker, N.Y., 1971) pp1-64; T. T. Tidwell, Org. React. 39, 297-572 passim (1990); and T. V.Lee, Comp. Org. Syn. 7, 291-303 passim (1991)). In a preferredembodiment, compounds of formula (4-1) are treated with Dess-Martinperiodinane in dichloromethane at about 0° C. to about 25° C forapproximately 0.5 to 4 hours to produce compounds of formula (5-1).

Scheme 6 illustrates a procedure for the acylation of the C-3 hydroxygroup of compounds of formula (6-1). The C-3 hydroxy group is acylatedunder basic conditions using a suitable acylating agent lo introduce theacyl group of the formula —C(O)—T—R₂, where T is O, N, S or —(CH₂)_(t),where t=0 to 4 and R₂ is as previously described, in an aprotic solventas previously described for acylating compounds of formula (3-2).Typical acylating agents include, but are not limited to, acid halides,acid anhydrides, free acids and chloroformates. Typical bases include,but are not limited to, pyridine, DMAP, triethylamine, diisopropylethylamine, N-methyl morpholine, N-methyl pyrrolidine, 2,6-lutidine,1,8-diazabicyclo[5.4.0]undec-7-ene. (See, T. W. Greene and P. G. M. Wutsin Protective Groups in Organic Synthesis 3^(rd) ed., John Wiley & Son,Inc, 1999, and references therein).

Alternately, in compounds of formula (6-1) the C-3 hydroxy group may befurther derivatized to form, for example, ethers, esters, sulfonates,and the like, using methods well known in the art (see, for example, J.March, Advanced Organic Chemistry 4^(th) ed., Wiley & Son, Inc., 1992,and the references therein).

Another method of the present invention, as illustrated in Scheme 7,involves synthesis of the C-3 deoxygenated macrolide (7-2) which can beaccomplished via the two step procedure shown above. In the first step,the xanthate or thiocarbonate of formula (7-1) is formed by the reactionof alcohol of formula (6-1) with the appropriate thiocarbonyl compound.These reactions are typically run in a polar aprotic solvent, preferablytetrahydrofuran, acetonitrile, N,N-dimethylformamide, and the like.Formation of the xanthate can be accomplished, for example, by reactionof the alcohol (6-1) with, for example, but not limited to,carbondisulfide followed by methyliodide, or a dithiocarbonyl imidazoleetc. The thiocarbonate can be prepared by the reaction of the alcoholwith for example, but not limited to, thiocarbonyldimidazole followed bymethanol, ethanol or the like, or a thiochloroformate etc. One skilledin the art will appreciate that other reagents and conditions exist toperform these transformations and that the examples above are forillustrative purposes only and do not limit the scope of this invention.

In the second step, the thiocarbonate or xanthate of formula (7-1) isconverted to compound (7-2). Most typically this is done under radicalconditions using, for example, a silyl hydride such as SiH(TMS)₃,SiH₂Ph₂ or the like, a tin hydride such as Bu₃SnH, Ph₃SnH or the like,and a radical initiator such as AlBN or t-butyl peroxide. The preferredsolvent is toluene.

Compounds according to the formula (8-1) may be prepared from compoundsof formula (6-1) by selective hydrogenation methods known in the art,for example, but not limited to, metal hydrides, such as, borane, orhydrogen in the presence of a catalyst, such as, palladium-on-charcoal,platinum metal or oxide, Wilkinson's catalyst and the like (see,Rylander, Hydrogenation Methods; Academic Press: New York, 1985; J.March, Advanced Organic Chemistry 4^(th) ed., Wiley & Son, Inc., 1992;and the references therein).

Compounds (9-2, 9-3 and 9-4, where R is R₃ as previously defined andR_(p) and R₂′ are as previously defined) can be prepared by thewell-established 1,3-dipolar cycloaddition reactions, such as, but notlimited to, reaction of compound (9-1) and an oxime in the presence ofNCS in an aprotic solvent such as ethyl acetate, methylene chloride,THF, or the like, to form compound (9-1) (see (a) Tufariello, Joseph J.Nitrones in 1,3 [One, Three]-Dipolar Cycloaddit. Chem. (1984), 2,83-168. (b) Huisgen, Rolf. 1,3-Dipolar cycloaddition—introduction,survey, mechanism in 1,3 [One, Three]-Dipolar Cycloaddit. Chem. (1984),1, 1-176, and the references therein). Compounds (9-2) and (9-3) can beprepared similarly by reacting compound (9-1) with an azide or a nitronerespectively.

Other 1,3-Dipolar cycloaddition reactants useful in formingcycloaddition products with compounds of the present invention such ascompound (9-1) include, but are not limited to, diazoalkane, nitrousoxide, nitrile imine, nitrile ylide, nitrile oxide, etc. (see, Padwa1,3-Dipolar Cycloaddition Chemistry, 2 vols.; Wiley: New York, 1984, andJ. March, Advanced Organic Chemistry, 4^(th) edition; Wiley: New York,1992, and the references therein).

Compound (10-1) is prepared by Diels-Alder reactions, where R_(y) andR_(z) independently may be selected from CHO, COOH, COOR, COR, COAr, CN,NO₂, Ar, CH₂OH, CH₂Cl, CH₂NH₂, CH₂CN, CH₂COOH, halogen, —C═C—, R and thelike, R being R₃ as previously defined herein (see (a) Danishefsky,Samuel. Cycloaddition and cyclocondensation reactions of highlyfunctionalized dienes: applications to organic synthesis in Chemtracts:Org. Chem. (1989), 2 (5), 273-97, (b) Larock Comprehensive OrganicTransformation; VCH: New York, 1989, 263-272, and the referencestherein).

Aziridines such as compound (10-2) can be obtained from, for example,but not limited to, the reaction of compound (9-1) with iodine in thepresence of a primary amine in an aprotic solvent such as methylenechloride, THF, and the like.

Lactones such as compound (10-3) can be obtained by a variety ofreactions such as but not limited to, reaction with: manganese (III)acetate in the presence of acetic acid, lead tetraacetate,α-bromocarboxylic acids in the presence of benzoyl peroxide etc. (see,Larock Comprehensive Organic Transformation; VCH: New York, 1989; J.March, Advanced Organic Chemistry, 4^(th) edition; Wiley: New York,1992, and the references therein).

Compound (11-1) is prepared by osmium tetraoxide (OSO₄) catalyzeddihydroxylation of the double bond. In a typical procedure, compound(6-1) is treated with about 1 to about 3 equivalents of NMO in a solventlike t-butanol or acetone, with or without water, in the presence ofabout 1 to about 10% of 0504. Compound (11-2) can then be obtained fromcompound (11-3) through standard acylation or alkylation of the diol,where R₇ and R₈ are independently selected from R₃ and where R₃ is aspreviously defined herein.

Compound (11-3) is prepared by epoxidation of the double bond withreagents such as, but not limited to, peracids, e.g. m-CPBA, hydrogenperoxide, t-BuOOH etc. (see (a) Chem. Rev. 1989, 89, 431; (b) Chem. Rev.1992, 92, 873, and references therein).

Compounds of formula (9-1) can be converted to compounds of formula(12-1) by, for example, but not limited to, hydroboration with a boranereagent, for example, B₂H₆-THF, 9-BBN (9-borabicyclo[3.3.1]nonane), andthe like, (optionally complexed with THF, dimethylsulfide, phosphines,tertiary amines and the like) and followed by treatment with hydrogenperoxide and NaOH.

Compounds of formula (12-1) may be oxidized to compounds of formula(12-2) with a suitable oxidizing agent. Compounds of formula (12-2) canbe reacted with appropriate substituted hydroxylamines of the generalformula RONH₂ where R is preferably R₃, where R₃ is as previouslydefined, in a protic solvent under acidic or basic conditions to givecompounds of the formula (12-3). Representative acids include, but arenot limited to, hydrochloric acid, phosphoric acid, sulfuric acid,p-toluenesulfonic acid, etc. Representative bases include, for example,triethylamine, pyridine, diisopropylethyl amine, 1,5-lutidine, and thelike. Appropriate solvents include, but are not limited to, methanol,ethanol, water, tetrahydrofuran, 1,2-dimethoxyethane and ethyl acetate.

Also, compounds of the formula (12-2), where the ketone is on the6,11-4-carbon bridge, may be further derivatized, for example, but notlimited to, conversion to the corresponding amines by reductiveamination, reaction with hydrazines to form the correspondinghydrazones, conversion to substituted alkenes by Wittig reaction,alkylation with Grignard reagent etc., by standard methods known in theart described in references incorporated herein.

Scheme 13 illustrates the procedure by which compounds of formula (5-1),wherein A, B, Q, and R₂′ are as previously defined, may be converted tocompounds of formula (13-1), wherein Q, W, Z, and R₂′ are as previouslydefined, by treatment with a halogenating reagent. This reagent acts toreplace a hydrogen atom with a halogen atom at the C-2 position of theketolide. Various halogenating reagents may be suitable for thisprocedure.

Fluorinating reagents include, but are not limited to,N-fluorobenzenesulfonimide in the presence of base, 10% F₂ in formicacid, 3,5-dichloro-1-fluoropyridinium tetrafluoroborate,3,5-dichloro-1-fluoropyridinium triflate, (CF₃SO₂)₂NF,N-fluoro-N-methyl-p-toluenesulfonamide in the presence of base,N-fluoropyridinium triflate, N-fluoroperfluoropiperidine in the presenceof base.

Chlorinating reagents include, but are not limited to, hexachloroethanein the presence of base, CF₃CF₂CH₂lCl₂, SO₂Cl₂, SOCl₂, CF₃SO₂Cl in thepresence of base, Cl₂, NaOCl in the presence of acetic acid.

Brominating reagents include, but are not limited to, Br₂.pyridine.HBr,Br₂/acetic acid, N-bromosuccinimide in the presence of base,LDA/BrCH₂CH₂Br, or LDA/CBr₄.

A suitable iodinating reagent is N-iodosuccinimide in the presence ofbase, or I₂, for example.

Suitable bases for the halogenating reactions requiring them arecompounds such as alkali metal hydrides, such as NaH and KH, or aminebases, such as LDA or triethylamine, for example. Different reagents mayrequire different type of base, but this is well known within the art.

A preferred halogenating reagent is N-fluorobenzenesulfonimide in thepresence of sodium hydride.

Suitable solvents are dimethylformamide, dimethyl sulfoxide,pyrrolidinone and the like.

It will be appreciated by one skilled in the art that all ketolidecompounds delineated herein may be halogenated at the 2-carbon if sodesired.

All references cited herein, whether in print, electronic, computerreadable storage media or other form, are expressly incorporated byreference in their entirety, including but not limited to, abstracts,articles, journals, publications, texts, treatises, internet web sites,databases, patents, and patent publications.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

EXAMPLE 1

Compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N═CH(OMe)—, X=Z=H,

L=CH₂CH₃, and R₂′=Bz.

Step 1a:

A compound of formula (1-2), wherein R₈=R₂′=R₄″=Bz.

To a solution of erythrmycin A oxime (27.5 g, 36.7 mmol), benzoicanhydride (34.9 g, 154 mmol) in 200 ml THF is added triethylamine (22.5ml, 161.6 mmol) and DMAP (4.49 g, 36.7 mmol) at room temperature andstirred for 24 hours. The reaction mixture is condensed to about 100 ml.Then ethyl acetate (300 ml) is added, and the resulting organic phase iswashed with saturated NaHCO₃ (300 ml×3) and brine (300 ml×1). Theorganic phase is dried over anhydrous Na₂SO₄ and the solvent is removedin vacuo to give the title compound (90 g).

MS (ESI) m/z 1062.27 (M+H)⁺

Step 1b:

Compound of formula (1-3)

To a solution of (9.25 g, 105 mmol) and di-tert-butyl dicarbonate (60 g,275 mmol) in 150 ml of dichloromethane is added 6N NaOH (140 ml) andtetrabutylammonia hydrogensulfate (3.4 g, 10 mmol). The mixture isstirred at room temperature overnight. The organic layer is separated,washed with NaHCO₃ (200 ml×3) and brine(200 ml), dried over anhydrousMgSO₄, concentrated and dried over vacuum to give the title compound

¹H NMR (CDCl₃): 5.65(t, 2H); 4.54(d, 4H); 1.18(s, 18H).

¹³C NMR(CDCl₃): δ153.3, 128.1, 82.4, 62.4, 27.8.

Step 1c:

Compound of formula (1-4), wherein R₈=R₂′=R₄″=Bz.

To a solution of erythromycin oxime 2′, 4″, 9-tribenzoate from Step 1a(5.31 g, 5 mmol), the compound from step 1b (4.33 g, 15 mmol) and dppb(213 mg, 0.5 mmol) in THF (40 ml), is added Pd₂(dba)₃ (229 mg, 0.25mmol) under nitrogen. The mixture is refluxed for 1.5 hours and dilutedwith ethyl acetate (150 ml), washed with saturated NaHCO₃ (200 ml×2) andbrine (200 ml), and dried over anhydrous Na₂SO₄. The solvent is removedin vacuo, and the residue is purified by flash chromatography (SiO₂hexane:acetone/2:1) to give the title compound (5.0 g).

MS (ESI) m/z 1113.82 (M+H)⁺

Step 1d:

A compound of formula (1-4), wherein R₈=OH and R₂′=R₄″=Bz.

To a solution of compound from step 1c (5.0 g, 4.5 mmol) in 40 mlisopropanol is added 1 M NaOH (5 ml) at 0° C. The mixture is stirred atthat temperature for 30 minutes and then is quenched by addition ofsaturated NaHCO₃ (50 ml). The mixture is extracted with ethyl acetate(60 ml×1) and dried over anhydrous Na₂SO₄. The solvent is removed invacuo, and the residue is purified via flash chromatography (SiO₂,hexane/acetone=4/1) to give the title compound (3.0 g).

MS (ESI) m/z 1009.86(M+H)⁺.

¹³C NMR(CDCl₃): δ176.4, 171.8, 166.5, 165.7, 165.5, 138.2, 133.6, 132.8,131.1, 131.0, 130.2, 130.0, 128.6, 128.5, 100.8, 96.4, 80.5, 79.7, 79.3,78.5, 77.5, 75.6, 73.3, 72.8, 71.7, 71.0, 68.0, 64.0, 63.6, 62.7, 60.6,50.0, 45.2, 41.2, 39.7, 35.6, 35.4, 34.7, 32.2, 27.2, 23.0, 21.6, 21.5,21.3, 20.8, 20.7, 18.5, 18.2, 15.8, 15.5, 14.4, 11.3, 9.8.

Step 1e:

Compound of formula I, wherein W is —CH₂CH═CHCH₂—. D=

L=CH₂CH₃, and R₂′=Bz.

To a solution of the compound from step 1d (10 mg, 0.1 mmol) in CH₂Cl₂(5 ml) at −10° C. is added p-toluenesulfonic anhydride. (43 mg, 0.13mmol, 1.3 eq) is added to a solution of compound of step 1d (101 mg, 0.1mmol) and anhydrous Et₃N (21 μl, 0.15 mmol). The resulting mixture isstirred at −10° C. for 40 min. Anhydrous MeOH (4 mL) is added to thereaction mixture at −10° C. and the reaction mixture is slowly warmed upand stirred at 20° C. for 1 h. The reaction mixture is diluted withCH₂Cl₂ (20 mL), washed with saturated NaHCO₃ (3×20 mL) and brine (20mL), and dried over Na₂SO₄. The solvent is removed in vacuo, and theresidue is purified via flash chromatography (SiO2, hexane/acetone=4/1)to give the title compound (100 mg).

MS (ESI) m/z 1023.14 (M+H)⁺

EXAMPLE 2

Compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=

L=CH₂CH₃, and R₂′=Bz.

A solution of compound from step Ie (100 mg, 0.1 mmol) in 5 ml methanolis added NaBH₄ (17 mg, 0.5 mmol) at room temperature. The resultingmixture is stirred at room temperature for 2 hours. Subsequently,Tri(hydroxymethyl)aminomethane (5% in water) (20 ml) is added andstirred vigorously for 1 hour and the mixture is extracted with ethylacetate (30 ml). The organic phase is dried over Na₂SO₄ andconcentrated. The residue is purified on silica gel to give the titlecompound (90 mg).

MS (ESI) m/z 995.40 (M+H)⁺

Compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—NHCH₂, X=Z=H,

L=CH₂CH₃, and R₂′=H.

A solution of compound of example 1 (90 mg) in 10 ml methanol isrefluxed for 3 hours. The solvent is removed and the residue is purifiedby flash chromatography (SiO_(2, 2)M ammonia in methanol:CH₂Cl₂=5:95) togive the title compound (80 mg).

MS (ESI) m/z 891.44 (M+H)⁺

¹³C NMR(CDCl₃): δ177.2, 165.3, 133.8, 132.2, 131.5, 129.1, 128.7, 127.3,101.9, 94.0, 79.6, 78.6, 78.4, 78.3, 76.2, 72.6, 72.0, 71.7, 70.1, 69.8,67.2, 64.7, 62.3, 60.8, 57.2, 48.6, 45.1, 43.0, 40.9, 39.4, 33.9, 28.1,27.9, 21.2, 21.1, 20.7, 20.4, 20.3, 17.3, 17.2, 14.3, 10.3, 8.1.

EXAMPLE 3

Compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—NHCH₂—, X=Z=H,Y=OH, L=CH₂CH₃, and R₂′=H.

To a solution of the compound from step 1c (18 mg, 0.02 mmol) in 1 mlethanol is added 2M HCl (1 ml). The mixture is heated to 60° C. andstirred for 3 hours after which to the mixture is added saturated Na₂CO₃(10 ml). The resulting mixture is then extracted with ethyl acetate (10ml), washed with brine (10 ml×2), dried over anhydrous Na₂SO₄, andconcentrated in vacuo. The residue is purified by flash chromatography(SiO₂, 2M ammonia in methanol: CH₂Cl₂=5:95) to give the title compound(12 mg).

MS (ESI) m/z 629.37(M+H)⁺.

13C NMR(CDCl₃): δ174.5, 127.2, 98.2, 89.4, 86.2, 79.5, 75.4, 74.5, 72.1,71.6, 69.5, 61.6, 54.5, 52.7, 47.5, 42.3, 40.9, 39.2, 32.1, 29.3, 27.0,20.9, 20.5, 19.5, 18.5, 17.3, 16.8, 9.8, 9.2.

EXAMPLE 4

Compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—NHCH₂—, X and Yare taken together with the carbon to which they are attached are C═O,L=CH₂CH₃, and R₂′=H.

To a solution of compound of example 2 (12 mg) in 5 ml dichloromethaneis added acetic acid (20 μl) and Dess-Martin reagent (15 mg) at roomtemperature. The mixture is stirred at room temperature for 30 minutesand Na₂S₂O₃ (20 mg) is added. After stirring for 1 hour, to the mixtureis added saturated NaHCO₃ (10 ml). The resulting reaction mixture isthen extracted with dichloromethane (10 ml), dried over anhydrousNa₂SO₄. The solvent is removed and the residue is purified by flashchromatography (SiO₂, 2M ammonia in methanol:CH₂Cl₂=5:95) to give thetitle compound (8 mg). MS (ESI) m/z 627.31 (M+H)⁺

¹³C NMR(CDCl₃): δ211.1, 171.6, 125.8, 97.6, 89.2, 85.6, 79.6, 74.5,71.5, 70.3, 68.9, 61.2, 55.4, 52.3, 50.6, 46.8, 40.2, 39.8, 38.9, 32.1,26.5, 21.1, 20.8, 19.5, 18.9, 18.2, 17.5, 9.6, 9.2.

EXAMPLE 5

A compound of formula I, wherein W is —CH₂CH═CHCH₂, D=−NHC(O)−, X=Z=H,L=−CH₂CH₃,

R₂′=H.

Step 5a:

A compound of formula (1-2), wherein R₂′=R₄″=R₈=Ac.

To a solution of erythromycin A oxime (74.9 g, 0.1 mol) in 400 ml THF isadded acetic anhydride (35.9 ml, 0.38 mol), triethylamine (55.7 ml, 0.4mol) and DMAP (3.7 g, 0.03 mol) at room temperature. The mixture isstirred at room temperature for 16 hours, condensed to −200 ml, anddiluted with 300 ml of ethyl acetate. The resulting mixture is thenwashed with NaHCO₃ (Sat.) (500 ml×4) and brine (500 ml), and dried onanhydrous Na₂SO₄. The solvent is evaporated in vacuo and the residue isrecrystallized from ethyl acetate to give title compound (78 g).

MS (ESI) m/z 875.46 (M+H)⁺.

¹³C NMR(CDCl₃): δ178.5, 175.4, 170.6, 170.2, 168.2, 100.2, 96.1, 83.3,79.3, 78.7, 75.2, 74.5, 72.9, 70.0, 67.6, 634, 63.2, 60.6, 49.5, 44.7,40.9, 35.4, 31.8, 28.5, 22.8, 21.7, 21.6, 21.5, 21.3, 21.2, 21.1, 19.9,18.6, 18.4, 16.7, 14.9, 14.4, 14.3, 10.8, 9.2.

Step 5b:

A compound of formula (1-4), wherein A=B=H, and R₂′=R₄″=R₈=Ac.

To a solution of erythromycin oxime 2′, 4″, 9-triacetate from Step 5a(4.38 g, 5 mmol), the compound from step 1b (4.33 g, 15 mmol) and dppb(213 mg, 0.5 mmol) in THF (40 ml), is added Pd₂(dba)₃ (229 mg, 0.25mmol) under nitrogen. The mixture is refluxed for 1.5 hours and dilutedwith ethyl acetate (150 ml). The resulting mixture is then washed withsaturated NaHCO₃ (200 ml×2) and brine (200 ml), and dried over anhydrousNa₂SO₄. The solvent is removed in vacuo, and the residue is purified byflash chromatography (SiO₂ hexane:acetone/2:1) to give the titlecompound (4.0 g).

MS (ESI) m/z 927.54 (M+H)⁺

Step 5c:

A compound of formula (1-4), wherein A=B=H, and R₂′=R₄″=Ac, and R₈=H.

To a solution of compound from step 5b (456 mg, 0.46 mmol) in THF (5 ml)and isopropanol (5 ml) at 0° C. is added 1N LiOH (2.5 ml). The reactionmixture is stirred at 0° C. for 30 minutes and quenched with saturatedNaHCO₃ (10 ml). The resulting reaction mixture is then extracted withethyl acetate (15 ml) and the organic layer is dried over anhydrousNa₂SO₄. The solvent is removed in vacuo, and the residue is purified byflash chromatography (SiO₂ hexane:acetone/1:1) to give the titlecompound (433 mg).

MS (ESI) m/z 885.29 (M+H)⁺.

¹³C NMR(CDCl₃): δ176.3, 170.7, 170.2, 165.3, 138.4, 130.4, 100.4, 96.5,79.8, 79.3, 78.8, 78.3, 75.6, 74.5, 73.0, 72.0, 67.7, 63.3, 63.0, 60.5,49.6, 45.2, 40.8, 39.6, 35.4, 35.1, 34.9, 31.1, 27.1, 22.9, 21.6, 21.2,21.1, 21.0, 20.8, 20.4, 18.1, 15.2, 14.3, 11.1, 9.3.

Step 5d:

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=−NHC(O)−, X=Z=H,L=−CH₂CH₃,

R₂′=Ac.

To a solution of the compound from step 5c (120 mg, 0.13 mmol) inacetone is added a solution of TsCl (49 mg, 0.27 mmol) in 0.4 ml acetoneand a solution of NaHCO₃ (44 mg, 0.52 mmol) in 1.4 ml water at 0° C. Thereaction mixture is stirred at 0° C. for 2 hours and then warmed to roomtemperature overnight. The reaction mixture is then diluted with 15 mlmethylene chloride, washed with brine (20 ml×2), and dried over Na₂SO₄.The solvent is subsequently removed in vacuo and the residue is purifiedby flash chromatography (SiO₂, hexane/acetone=1/1) to give the titlecompound (70 mg).

MS (ESI) m/z 885.44(M+H)⁺

¹³C NMR(CDCl₃): δ178.9, 176.8, 170.8, 170.2, 135.7, 131.9, 100.6, 94.5,79.9, 79.1, 78.7, 78.5, 76.3, 75.1, 74.3, 73.1, 72.0, 70.8, 67.6, 63.4,62.9, 61.5, 49.6, 45.7, 45.5, 42.5, 40.9, 39.5, 37.2, 35.1, 31.7, 31.1,29.4, 22.0, 21.7, 21.6, 21.5, 21.4, 21.1, 20.9, 18.3, 15.1, 14.5, 11.3,9.3.

Step 5e:

Title compound:

A solution of compound of example 5d (60 mg) in 5 ml methanol isrefluxed for 3 hours. The solvent is removed and the residue is purifiedby flash chromatography (SiO₂, 2M ammonia in methanol:CH₂Cl₂=5:95) togive the title compound (50 mg).

MS (ESI) m/z 843.32(M+H)⁺

EXAMPLE 6

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N(Q)CH₂—, Q=CH,X=Z=H, Y=OH, L=CH₂CH₃, R₂′=H.

To a solution of the compound of Example 3 (63 mg, 0.1 mmol) in 10 mlmethanol is added formaldehyde (37% in water) (100 μl), acetic acid (100μl) and NaCNBH₃ (50 mg) at room temperature. The mixture is stirred atroom temperature for 4 hours after which is added 5% Tris (30 ml). Afterstirring vigorously for 1 hour, the mixture is extracted with ethylacetate (40 ml) and dried over anhydrous Na₂SO₄. The solvent is removedin vacuo and the residue is purified by flash chromatography (SiO₂, 2Mammonia in methanol:CH₂Cl₂=5:95) to give the title compound (60 mg).

EXAMPLE 7

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N(Q)CH₂—, Q=CH₃,Z=H, X and Y taken together are oxo, L=CH₂CH₃, R₂′=H.

The title compound is prepared with the title compound of Example 6 viathe Dess-Martin oxidation conditions described in Example 4.

EXAMPLE 8

A compound of formula I, wherein W is CH₂CH═CHCH₂—, D=—N(Q)CH₂—,Q=CH₂Ph, Z=X=H, Y=OH, L=CH₂CH₃, R₂′=H.

A solution of the compound of Example 3 in MeOH is treated withbenzaldehyde, excess NaCNBH₃, and acetic acid at room temperature. Thereaction mixture is stirred at room temperature for 4-8 hours andsubsequently cooled to 0° C. The solution is then neutralized withaqueous NaHCO₃, extracted with methylene chloride, and the organic phaseis dried over Na₂SO₄. The solvents are removed in vacuo and the residueis purified via column chromatography on silica gel to provide the titlecompound.

EXAMPLE 9

A compound of formula I, wherein W is CH₂CH═CHCH₂—, D=—N(Q)CH₂, Q=CH₂Ph,Z=H, X and Y are taken together are oxo, L=CH₂CH₃, R₂′=H.

The title compound is prepared with the title compound of Example 8 viathe Dess-Martin oxidation conditions described in Example 4.

EXAMPLE 10

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N(Q)CH₂—,Q=CH₂(2-pyridyl), Z=X=H, Y=OH, L=CH₂CH₃, R₂′=H.

The title compound is prepared via the procedure set forth in Example 8with the title compound of Example 3 and 2-pyridine carboxaldehyde.

EXAMPLE 11

A compound of formula I, W is —CH₂CH═CHCH, D=—N(Q)CH₂—,Q=CH₂(2-pyridyl), Z=H, X and Y taken together are oxo, L=CH₂CH₃, R₂′=H.

The title compound is prepared with the title compound of Example 10 viathe Dess-Martin oxidation conditions described in Example 4.

EXAMPLE 12

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N(Q)CH₂—,Q=CH₂(3-quinolyl), Z=H, X and Y taken together are oxo, L=CH₂CH, R₂′=H.

The title compound is prepared via the procedure set forth in Example 8with the title compound of Example 3 and 3-quinoline carboxaldehyde.

EXAMPLE 13

A compound of formula I, wherein W is —CH₂CH═CHCH₂, D=—N(Q)CH₂—,Q=CH₂(3-quinolyl), Z=H, X and Y taken together are oxo, L=CH₂CH₃, R₂′=H.

The title compound is prepared with the title compound of Example 12 viathe Dess-Martin oxidation conditions described in Example 4.

EXAMPLE 14

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N(Q)CH₂—,Q=CH₂(CH═CH)Ph, Z=X=H, Y=OH, L=CH₂CH₃, R₂′H.

The title compound is prepared via the procedure set forth in Example 8with the title compound of Example 3 and cinnamaldehyde.

EXAMPLE 15

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N(Q)CH₂—,Q=CH₂(CH═CH)Ph, Z=H, X and Y taken together are oxo, L=CH₂CH₃, R₂′=H.

The title compound is prepared with the title compound of Example 14 viathe Dess-Martin oxidation conditions described in Example 4.

EXAMPLE 16

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N(Q)CH₂—,Q=CH₂CH═CH(2-pyridyl), Z=X=H, Y=OH, L=CH₂CH₃, R₂′=H.

The title compound is prepared via the procedure set forth in Example 8with the title compound of Example 3 and 3-(2-pyridyl)acrolein.

EXAMPLE 17

A compound of formula I, wherein A and B taken together with the carbonatom to which they are attached=C═CH₂, D=—N(Q)CH₂—,Q=CH₂CH═CH(2-pyridyl), Z=H, X and Y taken together are oxo, L=CH₂CH₃,R₂′=H.

The title compound is prepared with the title compound of Example 16 viathe Dess-Martin oxidation conditions described in Example 4.

EXAMPLE 18

A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D=—N(Q)CH₂—,Q=CH₂C≡C(3-quinolyl), Z=X=H, Y=OH, L=CH₂CH₃, R₂′=H.

The title compound is prepared via the procedure set forth in Example 8with the title compound of Example 3 2 and 3-(3-quinolyl)propynaldehyde.

EXAMPLE 19

A compound of formula I, wherein W=—CH₂CH═CHCH₂—, D=—N(Q)CH₂—,Q=CH₂C≡C(3-quinolyl), Z=H, X and Y taken together are oxo, L=CH₂CH₃,R₂′=H.

The title compound is prepared with the title compound of Example 18 viathe Dess-Martin oxidation conditions described in Example 4.

Although the invention has been described with respect to variouspreferred embodiments, it is not intended to be limited thereto, butrather those skilled in the art will recognize that variations andmodifications may be made therein which are within the spirit of theinvention and the scope of the appended claims.

What is claimed:
 1. A compound of formula I, or a pharmaceuticallyacceptable salt, ester, or prodrug thereof:

wherein: W is (a) —CH₂—C(A)═C(B)—CH₂—, wherein, A and B areindependently selected from:
 1. hydrogen;
 2. deuterium;
 3. halogen; 4.R₁, wherein R₁ is selected from: a. —C₁-C₆ alkyl, optionally substitutedwith one or more substituents selected from halogen, aryl, substitutedaryl, heteroaryl, or substituted heteroaryl; b. —C₂-C₆ alkenyl,optionally substituted with one or more substituents selected fromhalogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;or c. —C₂-C₆ alkynyl, optionally substituted with one or moresubstituents selected from halogen, aryl, substituted aryl, heteroaryl,or substituted heteroaryl;
 5. R₂, wherein R₂ is selected from: a. aryl;b. heteroaryl; c. substituted aryl; d. substituted heteroaryl; e.heterocycloalkyl; or f. substituted heterocycloalkyl; 6.—(C₁-C₃-alkyl)-M—(C₁-C₃-alkyl)-R₂, wherein M is selected from —O—, —NH—,—N(CH₃)—, —NHC(O)— or —S(O)_(n)—, wherein n=0, 1 or 2, and R₂ is aspreviously defined:
 7. —(C₁-C₃-alkyl)-M—R₂, wherein M and R₂ are aspreviously defined;
 8. —C(O)—V—R₃, wherein V is absent, O or S, and R₃is H, R₁ or R₂; where R₁ and R₂ are as previously defined; or 9.—(O)—NR₁₁R₁₂, wherein R₁₁ and R₁₂ are each independently selected from:a. hydrogen; b. —C₁-C₆-alkyl, optionally substituted with one or moresubstituents selected from halogen, aryl, substituted aryl, heteroaryl,or substituted heteroaryl; c. —C₂-C₆-alkenyl, optionally substitutedwith one or more substituents selected from halogen, aryl, substitutedaryl, heteroaryl, or substituted heteroaryl; d. —C₂-C₆-alkynyl,optionally substituted with one or more substituents selected fromhalogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;or  in the alternative, R₁₁ and R₁₂taken together with the nitrogen atomto which they are connected form a 3-to 7-membered ring which mayoptionally contain one or more double bonds and one or moreheterofunctions selected from —O—, —NH—, —N(C₁-C₆-alkyl)-, —N(R₂)—,—S(O)_(n)—, wherein n and R₂ are as previously defined; (b)—CH₂—CH(A)—C(B)═CH—, wherein A and B are as previously defined; (c)—CH₂—CH(E)—CH(G)—CH₂—, wherein E and G are independently selectedfrom
 1. A, wherein A is as previously defined;
 2. —OH;
 3. —OR^(p),wherein R^(p) is a hydroxy protecting group;
 4. —O—R₉, wherein R₉ is R₁or R₂, and wherein R₁ and R₂ are as previously defined;
 5. —S(O)_(n)R₉,wherein n and R₉ are as previously defined;
 6. —NHC(O)R₃, wherein R₃ isas previously defined;
 7. —NHC(O)NR₁₁R₃, wherein R₁₁ and R₃ are aspreviously defined;
 8. —NHS(O)₂R₉, wherein R₉ is as previously defined;9. —NHR₁₃, wherein R₁₃ is an amino protecting group; or
 10. —NR₁₁R₁₂,wherein R₁₁, and R₁₂ are as previously defined; (d)

 wherein —J— is selected from —O—; —O—C(O)—CH(R₇)—; —N(R₇)—;—O—C(O)—N(R₇)—; —O—C(O)—O—; —N(R₇)—N═N—; —C(R₇)═N—O—; or—CH(R₇)—N(R₈—O—; wherein R₇ and R₈ are independently selected from R₃,wherein R₃ is as previously defined; or, in the alternative, —J— istaken with the two carbon atoms to which it is attached to form a cyclicmoiety selected from a. C₃-C₁₂ cycloalkyl; b. C₃-C₁₂ cycloalkenyl; or c.heterocycloalkyl; or (e) —CH₂—C(R₄)(R₅)—CH₂—CH₂—, wherein R₄ and R₅taken together with the carbon atom to which they are attached areselected from:
 1. C═O;
 2. C(OR₁)₂, wherein R₁ is as previously defined;3. C(SR₁)₂, wherein R₁ is as previously defined;
 4. C(OR₁₂)(OR₁₃), whereR₁₂ and R₁₃ taken together are —(CH₂)_(m)—, and where m is 2 or 3; 5.C(SR₁₂)(SR₁₃), where R₁₂ and R₁₃ taken together are —(CH₂)_(m)—, where mis as previously defined;
 6. C═CHR₃, wherein R₃ is as previouslydefined;
 7. C═N—O—R₃, wherein R₃ is as previously defined;
 8. C═NNHR₃,wherein R₃ is as previously defined;
 9. C═NNHC(O)R₃, wherein R₃ is aspreviously defined;
 10. C═NNNHC(O)NR₁₁R₃, wherein R₁₁ and R₃ are aspreviously defined;
 11. C═NNHS(O)₂R₉, wherein R₉ is as previouslydefined;
 12. C═NNHR₁₃, wherein R₁₃ is as previously defined; or 13.C═NR_(9,) wherein R₉ is as previously defined; L is (a) —CH₃; (b)—CH₂CH₃; (c) —CH(OH)CH₃; (d) —C₁-C₆-alkyl, optionally substituted withone or more substituents selected from aryl, substituted aryl,heteroaryl, or substituted heteroaryl; (e) —C₂-C₆ alkenyl, optionallysubstituted with one or more substituents selected from aryl,substituted aryl, heteroaryl, or substituted heteroaryl; or (f)—C₂-C₆alkynyl, optionally substituted with one or more substituentsselected from aryl, substituted aryl, heteroaryl, or substitutedheteroaryl; D is —N(Q)CH₂—, N(R′)C(O)—, or —N═C(OR′)—, wherein R′ is R₁₁as previously defined; Q is (a) hydrogen; (b) —C₁-C₁₂-alkyl,C₂-C₁₂-alkenyl, or C₂-C₁₂-alkynyl, all optionally substituted with one,two or three substituents independently selected from:
 1. halogen; 2.—OR₆, wherein R₆ is selected from: a. hydrogen; b. —C₁-C₁₂-alkylcontaining 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionallysubstituted with one, two, or three substituents independently selectedfrom aryl, substituted aryl, heteroaryl, or substituted heteroaryl; c.aryl; d. substituted aryl; e. heteroaryl; f. substituted heteroaryl; g.heterocycloalkyl; or h. substituted heterocycloalkyl;
 3. —NR₄R₅, whereR₄ and R₅ are each independently R₆, where R₆ is as previously defined,or in the alternative R₄ and R₅, together with the atom to which theyare attached, form a heterocycloalkyl or substituted heterocycloalkylmoiety;
 4. ═N—O—R₆, where R₆ is as previously defined;
 5. —R₁, where R₁is as previously defined;
 6. —C₃-C₈-cycloalkyl;
 7. substituted—C₃-C₈-cycloalkyl;
 8. heterocycloalkyl;
 9. substituted heterocycloalkyl;10. —NHC(O)R₆, where R₆ is as previously defined;
 11. —NHC(O)OR₇, whereR₇ is selected from: a. —C₁-C₁₂-alkyl containing 0, 1, 2, or 3heteroatoms selected from O, S or N, optionally substituted with one,two, or three substituents independently selected from aryl, substitutedaryl, heteroaryl, or substituted heteroaryl; b. aryl; c. substitutedaryl; d. heteroaryl; e. substituted heteroaryl; f. heterocycloalkyl; org. substituted heterocycloalkyl;
 12. —NHC(O)NR₄R₅, where R₄ and R₅ areas previously defined;
 13. —OC(O)NR₄R₅, where R₄ and R₅ are aspreviously defined;
 14. —OC(O)R₇, where R₇ is as previously defined; 15.—OC(O)OR₇, where R₇ is as previously defined;
 16. —OC(O)NR₄R₅, where R₄and R₅ are as previously defined,
 17. —C(O)R₆, where R₆ is as previouslydefined,
 18. —CO₂R₆, where R₆ is as previously defined, or 19.—C(O)NR₄R₅, where R₄ and R₅ are as previously defined; X is hydrogen; Yis (a) hydrogen; (b) —OH; (c) —OR_(p), where R_(p) is as previouslydefined; (d) —OR_(y), where R_(y) is R₁ and R₂ as previously defined;(e) —OC(O)R_(y), where R_(y) is R₁ and R₂ as previously defined; (f)—OC(O)NHR_(y), where R_(y) is R₁ and R₂ as previously defined; (g)—S(O)_(n)R_(y), where n is previously defined and R_(y) is R₁ and R₂ aspreviously defined; (h) —

 where R₃″ is hydrogen or methyl; R₄″ is hydrogen or R_(p), where R_(p)is as previously defined; or (i) in the alternative, X and Y combinedtogether are oxo; Z is (a) hydrogen; (b) methyl; or (c) halogen; and R₂′is hydrogen or R_(p,) where R_(p,) is as previously defined.
 2. Acompound according to claim 1 represented by formula II:


3. A compound according to claim 1 represented by formula III:


4. A compound according to claim 1 represented by formula IV:


5. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1 or a pharmaceutically acceptable salt,ester or prodrug thereof, in combination with a pharmaceuticallyacceptable carrier.
 6. A method for controlling a bacterial infection ina subject, comprising administering to said subject a therapeuticallyeffective amount of a pharmaceutical composition according to claim 5.7. A process for the preparation of a compound of formula:

wherein L, Q, W, X, Y, Z and R₂′ are as defined in claim 1, comprisingthe steps of: (1) reacting a compound of the formula:

 wherein R⁸ is a. Hydrogen; b. —CH₂O(CH₂)₂OCH₃; c.—CH₂O(CH₂O)_(n)CH_(3,) where n is as previously defined; d. —C₁-C₁₂alkyl, optionally substituted with one or more substituents selectedfrom aryl, substituted aryl, heteroaryl and substituted heteroaryl; e.—C₃-C₁₂ cycloalkyl; f. —C(O)—C₁-C₁₂ alkyl; g. —C(O)—C₃-C₁₂ cycloalkyl;h. —C(O)—R₁, where R₁ is as previously defined; or i.—Si(R_(a))(R_(b))(R_(c)), wherein R_(a), R_(b) and R_(c) are eachindependently selected from C₁-C₁₂ alkyl; aryl, or substituted aryl; andL, R₂′, and R₄″ are as defined in claim 1; with

 wherein A and B are as defined in claim 1, in the presence of aphosphine ligand and Pd(O) catalyst under reflux conditions to prepare acompound of the formula:

 wherein A, B, L, R₈, R₂′, and R₄″ are as defined in claim 1; (2)reacting the compound prepared in step (1) with a mild acid to prepare acompound of the formula:

 wherein A, B, L, R₈, and R₂′ are as defined in claim 1; (3) reactingthe compound prepared in step (2) with an oxime activating agent andquenching with methanol to prepare a compound of the formula:

 wherein A, B, L, R′, and R₂′ are as defined claim 1; (4) reacting thecompound prepared in step (3) with a reducing agent to prepare compoundof the formula:

 wherein A, B, L, and R₂′ are as defined claim 1; (5) reacting thecompound prepared in step (4) with an alkylating agent, preferably analykyl halide in the presence of a base, or with an aldehyde viareductive amination in the presence of NaCNBH₃ to prepare a compound ofthe formula:

 wherein A, B, L, Q, and R₂′ is as defined claim 1; and (6) oxidizingthe hydroxyl in the 3 position of the compound prepared in step (5) viaDess-Martin oxidation, Corey-Kim oxidation, or a Moffat oxidation toprepare a compound of the formula:

 wherein A, B, L, Q, and R₂′ are as defined claim
 1. 8. A compound ofclaim 1 selected from: Compound of formula I, wherein W is—CH₂CH═CHCH₂—, D is —N═CH(OMe)—, X is H, Z is H, Y is

L is CH₂CH₃, and R₂′ is Bz; Compound of formula I, wherein W is—CH₂CH═CHCH₂—, D is —NHCH₂—, X is H, Z is H, Y is

L is CH₂CH₃, and R₂′ is Bz; Compound of formula I, wherein W is—CH₂CH═CHCH₂—, D is —NHCH₂—, X is H, Z is H, Y is

L is CH₂CH₃, and R₂′ is H; Compound of formula I, wherein W is—CH₂CH═CHCH₂—, D is —NHCH₂—, X is H, Z is H, Y is OH, L is CH₂CH₃, andR₂′ is H; Compound of formula I, wherein W is —CH₂CH═CHCH₂—, D is—NHCH₂—, X and Y are taken together with the carbon to which they areattached are C═O, L is CH₂CH₃, and R₂′ is H; A compound of formula I,wherein W is —CH₂CH═CHCH₂—, D is —NHC(O)—, X is H, Z is H, L is —CH₂CH₃,Y is

R₂′ is H; A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D is—N(Q)CH₂—, Q is CH₃, X is H, Z is H, Y is OH, L is CH₂CH₃, R₂′ is H; Acompound of formula I, wherein W is —CH₂CH═CHCH₂—, D is —N(Q)CH₂—, Q isCH₃, Z is H, X and Y taken together are oxo, L is CH₂CH₃, R₂′ is H; Acompound of formula I, wherein W is —CH₂CH═CHCH₂—, D is —N(Q)CH₂—, Q isCH₂Ph, Z is H, X is H, Y is OH, L is CH₂CH₃, R₂′ is H; A compound offormula I, wherein W is —CH₂CH═CHCH₂—, D is —N(Q)CH₂—, Q is CH₂Ph, Z isH, X and Y are taken together are oxo, L is CH₂CH₃, R₂′ is H; A compoundof formula I, wherein W is —CH₂CH═CHCH₂—, D is —N(Q)CH₂—, Q isCH₂(2-pyridyl), Z is H, X is H, Y is OH, L is —CH₂CH₃, R₂′ is H; Acompound of formula I, W is —CH₂CH═CHCH₂—, D is —N(Q)CH₂—, Q isCH₂(2-pyridyl), Z is H, X and Y taken together are oxo, L is CH₂CH₃, R₂′is H; A compound of formula I, wherein W is —CH₂CH═CHCH₂—, D is—N(Q)CH₂—, Q is CH₂(3-quinolyl), Z is H, X and Y taken together are oxo,L is CH₂CH₃, R₂′ is H; A compound of formula I, wherein W is—CH₂CH═CHCH₂—, D is —N(Q)CH₂—, Q is CH₂(3-quinolyl), Z is H, X and Ytaken together are oxo, L is CH₂CH₃, R₂′ is H; A compound of formula I,wherein W is —CH₂CH═CHCH₂—, D is —N(Q)CH₂—, Q is CH₂(CH═CH)Ph, Z is H, Xis H, Y is OH, L is CH₂CH₃, R₂′ is H; A compound of formula I, wherein Wis —CH₂CH═CHCH₂—, D is —N(Q)CH₂—, Q is CH₂(CH═CH)Ph, Z is H, X and Ytaken together are oxo, L is CH₂CH₃, R₂′ is H; A compound of formula I,wherein W is —CH₂CH═CHCH₂, D is —N(Q)CH₂—, Q is CH₂CH═CH(2-pyridyl), Zis H, X is H, Y is OH, L is CH₂CH₃, R₂′ is H; A compound of formula I,wherein A and B taken together with the carbon atom to which they areattached are C═CH₂, D is —N(Q)CH₂—, Q is CH₂CH═CH(2-pyridyl), Z is H, Xand Y taken together are oxo, L is CH₂CH₃, R₂′ is H; A compound offormula I, wherein W is —CH₂CH═CHCH₂—, D is —N(Q)CH₂—, Q isCH₂C≡C(3-quinolyl), Z is H, X is H, Y is OH, L is CH₂CH₃, R₂′ is H; or Acompound of formula I, wherein W is —CH₂CH═CHCH₂—, D is —N(Q)CH₂—, Q isCH₂C≡C(3quinolyl), Z is H, X and Y taken together are oxo, L is CH₂CH₃,R₂′ is H.